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Multiple sclerosis (MS) is an immune-mediated disease in which self-reacting T lymphocytes enter the central nervous system (CNS) and direct the damage of the myelin sheaths, which protect nerve axons. While there is no cure for MS currently, specific disease-modifying therapies are available that target the relapsing-remitting form of MS. However, these therapies are not effective in progressive forms of MS, which affect ~50% of MS patients in New Zealand, and thus there is an urgent need for novel treatments to be developed to treat these patients. MIS416 is a microparticle, which targets phagocytic cells by activating cytosolic receptors NOD2 and Toll-like receptor 9, and has recently completed a phase 2a trial in the treatment of progressive MS with promising results. The aim of this thesis was to elucidate the mechanism(s) by which MIS416 modified autoimmune disease using an animal model of MS, experimental autoimmune encephalomyelitis (EAE).  We determined that weekly intravenous doses of MIS416 were effective at reducing disease in a chronic model of MS, EAE, and we used this dosing regimen to further understand mechanisms involved in MIS416-induced EAE protection. It was found that MIS416 treatment induced a number of peripheral immune changes which had the potential to alter a T cell-mediated autoimmune disease, including increased levels of serum NO and IFN-γ, increased numbers of Tregs and macrophages as well as increased expression of PD-L1, an anti-proliferative ligand. Additionally, we also determined that MIS416 treatment significantly reduced T cell proliferation in vitro and in vivo.  To investigate which of these peripheral changes were involved in MIS416-mediated protection from EAE, we assessed each change individually in our disease model. We found that the central immune-modulating factor responsible for the protective effects of MIS416 treatment was IFN-γ (White, Webster, O'Sullivan, Stone, &amp; La Flamme, 2014) as IFN-γ-/- mice treated with MIS416 were not protected from EAE. This protective role of MIS416-induced IFN-γ was likely to have been mediated through downstream effects given that in the absence of IFN-γ many of these changes were not seen. In particular, the macrophage population did not expand in MIS416-treated IFN-γ-/- mice, and the expression of the immunoregulatory ligand, PD-L1, was not enhanced suggesting that macrophage expressed PD-L1 may be one of the ways in which MIS416-induced IFN-γ altered EAE. While NO was found to contribute to the MIS416-mediated suppression of T cell proliferation ex vivo and IFN-γ-/- mice did not have elevated levels of NO, the in vivo inhibition of iNOS by aminoguanidine did not ablate MIS416 protection suggesting that these pathways were not central to disease protection. Additionally, MIS416 treatment was shown to increase the number and function of Tregs, and in the absence of IFN-γ this expansion was reduced. Altogether, this research indicated that IFN-γ was key to MIS416-mediated protection possibly through an expansion of immunoregulatory macrophage populations, enhanced PD-L1 expression, and enhanced Treg numbers and function.  In addition to these peripheral immune effects, we found that MIS416 treatment also altered cellular trafficking to the CNS. MIS416-treated EAE mice had reduced CNS infiltration as measured by both flow cytometry and histology compared to untreated EAE mice, and MIS416 treatment also reduced the EAE-induced permeability of the blood brain barrier. Furthermore, our study determined that MIS416-induced trafficking of immune cells to the CNS in the absence of EAE, and this trafficking also occurred in an IFN-γ-dependent manner. Given the suppressive nature of cells found within the periphery of MIS416-treated mice, the cells which trafficked to the CNS in response to MIS416 treatment may have had beneficial roles in EAE by suppressing T cell responses from within the CNS.  In summary, the work outlined in this thesis revealed that MIS416 treatment induced an immunoregulatory state that was capable of suppressing T cell proliferation and reducing EAE disease. Moreover, this research highlighted that in the right context, a pro-inflammatory cytokine such as IFN-γ may be protective in autoimmune disease. Finally, when these findings are applied more widely, they indicate that the immune modulations induced by MIS416 may have potential in other diseases mediated by immune dysregulation in addition to MS.

Innate immunomodulation with MIS416: mechanism of action in experimental autoimmune encephalomyelitis